Clinical Case Report Medicine ®

OPEN

Pravastatin for prevention of HELLP syndrome

A case report
∗
Lucia Anna Otten, MDa, , Katrin van der Ven, MD, PhDb, Marietta Kühr, MDb, Ulrich Gembruch, MD, PhDa,
Waltraut Maria Merz, MDa

Abstract
Rationale: Pravastatin has emerged for prevention and treatment of preeclampsia; no reports are available on pravastatin and
HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome.
Patient concerns: The first pregnancy necessitated termination of pregnancy at gestational age (GA) 20+5 for HELLP.
Intrauterine fetal death at GA 22+5 occurred in the second pregnancy, whilst on temporizing management of HELLP.
Diagnoses: Severe, recurrent early-onset HELLP syndrome.
Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 11/08/2021

Interventions: In her fourth pregnancy, pravastatin was commenced at GA 13.

Outcomes: The course of pregnancy was uncomplicated, and a healthy, appropriate for gestational age fetus was delivered at
term.
Lessons: Pravastatin may be effective in prevention of HELLP. The hepatic uptake may be of particular advantage.
Abbreviations: AGA = appropriate for gestational age, ASA = acetylsalicylic acid, GA = gestational age, HELLP = hemolysis,
elevated liver enzymes, and low platelets, HMG-CoA = hydrophilic 3-hydroxy-3-methylglutaryl-coenzyme A, HOMA = homeostasis
model assessment, LMWH = low-molecular weight heparin, MTHFR = methylentetrahydrofolat-reductase, PlGF = placental growth
factor, s-Flt = soluble fms-like tyrosine kinase-1 receptor.
Keywords: HELLP syndrome, HMG-CoA-reductase inhibitor, pravastatin

1. Introduction history of 2 pregnancies that had been complicated by severe,

The syndrome of hemolysis, elevated liver enzymes, and low
platelets (HELLP) is regarded as particularly severe form of
preeclampsia, causing adverse pregnancy outcome for both the
mother and the fetus.[1] Soluble fms-like tyrosine kinase-1
receptor (s-Flt) is involved in the pathogenesis by inactivation of
vascular endothelial growth factor, resulting in angiogenic
imbalance and endothelial dysfunction.[2]
Pravastatin, a hydrophilic 3-hydroxy-3-methylglutaryl-coen-
zyme A (HMG-CoA)-reductase inhibitor, has been shown to
decrease levels of circulating s-Flt in animals.[3–6] Reassuring data
on teratogenicity and promising results in preliminary clinical
studies[7–10] prompted us to use pravastatin in a patient with a
Editor: Daryle Wane.
The authors have no funding and conflicts of interest to disclose.
a
Department of Obstetrics and Prenatal Medicine, b Department of Gynecologic
Endocrinology and Reproductive Medicine, University Bonn Medical School,
Bonn, Germany.
∗
Correspondence: Lucia Anna Otten, Department of Obstetrics and Prenatal
Medicine, University Bonn Medical School, Sigmund-Freud-Str. 25, D-53105
Bonn, Germany (e-mail: lucia.otten@ukb.uni-bonn.de).
Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial
and non-commercial, as long as it is passed along unchanged and in whole, with
credit to the author.
Medicine (2017) 96:42(e8229)
Received: 10 May 2017 / Received in final form: 12 September 2017 /
Accepted: 14 September 2017
http://dx.doi.org/10.1097/MD.0000000000008229
early-onset HELLP syndrome.
2. Case
In her first pregnancy (2012), the 36-year-old patient was referred
to our unit at gestational age (GA) 20+3 with epigastric pain,
nausea, and vomiting. Apart from a well-controlled Hashimoto
thyreoiditis her medical history was noncontributory. The
laboratory results were consistent with HELLP syndrome (Fig.
1); hypertension and proteinuria, not present initially, developed
subsequently. Hemolytic uremic syndrome, thrombotic throm-
bocytopenic purpura, and acute fatty liver of pregnancy were
excluded. Obstetric ultrasound revealed an appropriate for
gestational age (AGA) fetus with no obvious malformations;
blood flow velocity waveform indices of the fetal and
fetoplacental circulation were within normal range; the uterine
arteries, however, had highly abnormal pulsatility indices and
bilateral notching (Table 1). The maternal condition deteriorated
and necessitated termination of pregnancy at GA 20+5 (female,
weight: 330 g, 13th percentile). She made a rapid clinical recovery
and was discharged on day 1 after termination.
One year later, in her second pregnancy, she was referred for
severe fetal growth restriction and highly abnormal Doppler
indices at GA 20+2 (Table 1). Because of first-trimester vaginal
bleeding acetylsalicylic acid (ASA) had been withheld. Maternal
symptoms were absent, and laboratory results were normal. She
was monitored as outpatient until GA 22+2, when blood flow
indices in the ductus venosus deteriorated; in addition, she
developed symptoms of HELLP syndrome. The diagnosis was
confirmed by laboratory results (Fig. 1). Temporizing manage-
ment was initiated after extensive discussion; however, intrauter-

1
Otten et al. Medicine (2017) 96:42 Medicine

The HOMA (homeostasis model assessment) was slightly

500
AST/ALT elevated, a subsequent glucose tolerance test showed a marginally
450
abnormal 2-hour blood glucose concentration. The patient
400 received nutritional advice; she declined treatment with bigua-
350 nide derivatives.
Screening for thrombophilia did not reveal major inherited or
300 ALT 2012
AST 2012
acquired disorders except for homozygosity for the MTHFR
U/L

250
ALT 2013
(methylentetrahydrofolat-reductase) mutation C677T. Repeated
200
AST 2013
controls for antiphospholipid antibodies remained negative.
150 ALT 2016 However, D-dimers were mildly elevated in several analyses.
100 AST 2016 In 2015, then 39 years old, she miscarried at 8 weeks’
gestation; karyotyping revealed trisomy 22.
50
In early 2016, now 40 years old, the patient conceived again.
0 She was commenced on prophylactic treatment with low-
-3 -2 -1 0 1 2 3 5
molecular weight heparin (LMWH) (enoxaparin 40 mg s.c.
A day before and aer delivery daily), ASA (100 mg daily), and natural progesterone (400 mg
250 daily intravaginally). The preconception treatment with L-
Platelets
200
thyroxin (50 mg daily), selen (200 mg daily), myoinositol (1000
mg daily), and folic acid (2.5 mg daily) was continued.
150
Pravastatin (10 mg daily) was started at GA 12. Institutional
G/L

Platelets2012
100
Platelets2013
review board approval is not required for off-label use treatment.
50 Platelets2016
After extensive counseling about the medication, written consent
was obtained from the patient. Close surveillance (clinical,
0
laboratory, and ultrasound) was initiated. Throughout the entire
-3 -2 -1 0 1 2 5
course of pregnancy she was asymptomatic, and her laboratory
B day before and aer delivery
results remained within normal range. The obstetric ultrasound
Figure 1. Liver function tests (A) and platelets (B) in the days before and after revealed adequate growth of a fetus without major malforma-
delivery. ALT = alanine aminotransferase, AST = aspartate aminotransferase.
tions, and normal Doppler indices of the fetal, fetomaternal, and
uteroplacental vessels (Table 1). Gestational diabetes developed
in the third trimester and was controlled with insulin. At GA 37
ine fetal death occurred at GA 22+5 (female, weight: 325 g, <3rd +1, elective cesarean delivery was performed (male; 2920 g, 31st
percentile). Apart from a transient rise in blood pressure her percentile; Apgar scores 9/10/10 at 1, 5, and 10 minutes,
postoperative course was uncomplicated. respectively; umbilical artery pH 7.35). Both, patient and
Thereafter, the patient came for preconception counseling; she newborn, made an uncomplicated postoperative/postnatal
was informed about the high chance of another pregnancy failure course and were discharged on day 3.
and the substantial maternal risk, but she opted for another
attempt. Her request for immunosuppressive/immunomodulato-
ry treatment during her next pregnancy was denied because of 3. Discussion
lack of clinical and scientific evidence in HELLP syndrome; Pravastatin at a daily dosage of 10 mg, commenced early in the
peripheral lymphocyte typing had revealed normal results. second trimester, in addition to ASA and LMWH, resulted in an
Instead, an extensive diagnostic work-up for potential uncomplicated pregnancy and term delivery of an AGA healthy
cofactors of recurrent HELLP syndrome was offered. It included neonate in a patient with a history of severe, early-onset,
parental karyotyping, 3-dimensional ultrasound of the uterine recurrent HELLP syndrome.
cavity to rule out genital malformations or secondary changes, Presently, a HMG-Co-A-reductase-mediated decrease in s-Flt-
repeated cervical swabs for chlamydia trachomatis, ureaplasma 1 synthesis is hypothesized to be the mechanism underlying the
urealyticum, and mycoplasma hominis, all with negative results. positive effect of pravastatin in preeclampsia; in addition, a rise in
The endocrinological work-up revealed normal early follicular levels of circulating placental growth factor (PlGF) may
phase hormones; autoimmune thyreoiditis (Hashimoto) was contribute to the improvement of the proangiogenic profile
confirmed. Due to rising levels of anti-TPO antibodies, and the reversion of sequelae of inflammation and endothelial
substitution with L-thyroxin (maximum dosage of 50 mg daily) dysfunction.[5,7,9] The effect of pravastatin on soluble endoglin,
and selen (200 mg daily) was initiated. another cofactor of vascular homeostasis involved in the
pathogenesis of preeclampsia, is less clear, and may include an
organ-specific response.[8]
Table 1 In contrast to preeclampsia, HELLP syndrome is characterized
by hepatic and hematologic manifestations. Nevertheless,
Midtrimester pulsatility indices of the uterine arteries.
∗ HELLP syndrome and preeclampsia share the same pathophysi-
Pregnancy GA Right PI† Notching Left PI† Notching
ology, and HELLP syndrome is considered a particular
1 20+3 2.11 (>95) Yes 1.71 (>95) Yes manifestation of preeclampsia, respectively.
2 22+2 2.55 (>95) Yes 3.19 (>95) Yes We assume that the mechanism of action of pravastatin in
4 20+4 0.71 (52) No 1.40 (75) No HELLP syndrome is comparable to its effect in preeclampsia. The
∗
Gestational age: week plus day. hepatic uptake of pravastatin may be of particular advantage in
†
PI = pulsatiliy index (percentile). HELLP syndrome because 50% of the absorbed drug is lost by a
first-pass effect.[11]

2
Otten et al. Medicine (2017) 96:42
To our knowledge, this is the first report of pravastatin in
severe, early-onset, recurrent HELLP syndrome; the positive
outcome justifies further clinical trials in women at risk of
developing HELLP syndrome.
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